Here, we have demonstrated that SKP2 can in turn interact with Bcr-Abl, mediate K63-linked ubiquitination of Bcr-Abl, and promote its activation, thereby forming a forward feedback loop between Bcr-Abl and SKP2 in CML; we also have discovered that USP10 can serve as a DUB to remove K48-linked ubiquitin moieties from SKP2 and thereby stabilizing SKP2; hence, the Bcr-Abl-SKP2 feed-forward loop can be further amplified by USP10. Here, ZUP1 is linked to chronic myelogenous leukemia, BCR-ABL1 positive.